Eosinophilic esophagitis (EE) is an inflammatory disease of the esophagus that is being increasingly recognized especially during childhood. Notably, 70% of EE cases develop along with allergic asthma. The histological identification of increased eosinophils in the esophagus occurs in numerous clinical disorders such as food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, and gastroesophageal reflux (GER). Primary esophageal eosinophilic disorders (i.e. EE) are distinguished from secondary disorders (i.e. GER, drug reactions, infections, esophageal leiomyomatosis) based on several factors. For example, EE (also called idiopathic eosinophilic esophagitis, atopic esophagitis and allergic esophagitis) is characterized by high levels of eosinophils in the esophagus, eosinophilia involving the proximal and distal esophagus, and extensive esophageal histopathological changes (e.g. epithelial hyperplasia). Most patients with primary EE also have a high rate of atopic sensitization to aeroallergens and food antigens. Our goal is to provide the basis for developing novel therapeutic approaches for the treatment of EE. Our recent findings indicate that experimental eosinophilic inflammation occurs in the lungs and esophagus following pulmonary delivery of allergen or IL-13, but not the stomach or intestine, demonstrating an intimate immunological connection between the lung and esophagus. In these experimental systems, it is likely that sensitization occurs by pulmonary exposure since oral or intragastric allergen exposure alone fails to elicit eosinophilia. Collectively, our data has led to the central hypothesis that EE develops as a consequence of a Th2 immune response induced by allergen antigen translocation from the lung to the esophagus. In this grant application, we propose three Aims designed to; i) study the antigen translocation and the role of Th2 cytokines in the induction of EE; ii) study the role of antigen presenting cells and regional lymph nodes in EE induction, and finally, and iii) to explore the mechanism of EE in patients. This proposed study would provide new insight into eosinophil-induced esophageal inflammation, enabling us to develop novel approaches to treating eosinophil-associated esophageal diseases.